Fatty acid modification of Wnt1 and Wnt3a at serine is prerequisite for lipidation at cysteine and is essential for Wnt signalling

Doubravská, Lenka; Krausová, Michaela; Gradl, Dietmar; Vojtěchová, Martina; Tůmová, Lucie; Lukáš, Jan; Valenta, Tomáš; Pospíchalová, Vendula; Fafílek, Bohumil; Plachý, Jiřı́; Šebesta, Ondřej; Kor̆ínek, Vladimír

doi:10.1016/j.cellsig.2011.01.007

Cited by 87 publications

(75 citation statements)

References 56 publications

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“…Consistent with our observations, previous studies have shown that acyl-deficient Wnt proteins ineffectively initiate Wnt/β-catenin signaling activity in cultured mammalian cells. 21,22 Furthermore, as in the case of deleting β-catenin in the epidermis or inhibiting the Wnt/β-catenin pathway by overexpressing Dkk1, it converts hair follicles into interfollicular epidermis. 47 The function of modulating Wnt/β-catenin signaling activity may also indicate a notable and distinct role of RARRES3 in the cell fate decision.…”

Section: Discussionmentioning

confidence: 99%

“…10,46 Acyl modification of Wnt proteins was also shown to have a crucial role for proteins exiting from the endoplasmic reticulum, secreting to the extracellular domain or binding to the receptor. 21,22 Thus a regulatory mechanism of protein acylation may be necessary for cells to control Wnt/β-catenin signaling activity. In this study, we demonstrate that RARRES3 interacts with and mediates the protein deacylation of Wnt/β-catenin signaling molecules.…”

Section: Discussionmentioning

confidence: 99%

“…The fatty acid attachment serves as a secondary modification to affect protein conformation and maintain the stabilities of Wnt proteins and their co-receptors. [20][21][22] For the lipoprotein receptor-related protein 6 (LRP6), a co-receptor in the canonical Wnt/β-catenin signaling pathway, acylation is required for its exiting from endoplasmic reticulum and translocating to the plasma membrane (PM). 20 In particular, a dynamic palmitoylation cycle has been shown to regulate the shuttling of small GTPase H-Ras between intracellular compartments and either the PM or synaptic vesicle membranes.…”

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confidence: 99%

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Involvement of RARRES3 in the regulation of Wnt proteins acylation and signaling activities in human breast cancer cells

Hsu

Chan

et al. 2014

Cell Death Differ

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The Wnt/β-catenin signaling pathway has emerged as a key regulator of complex biological processes, such as embryonic development, cell proliferation, cell fate decision and tumorigenesis. Recent studies have shown that the deregulation of Wnt/β-catenin signaling is frequently observed and leads to abnormal cell growth in human breast cancer cells. In this study, we identified a novel regulatory mechanism of Wnt/β-catenin signaling through RARRES3 that targets and modulates the acylation status of Wnt proteins and co-receptor low-density lipoprotein receptor-related protein 6, resulting in the suppression of epithelialmesenchymal transition and cancer stem cell properties. Mutation of the conserved active site residues of RARRES3 indicates that RARRES3 serves as an acyl protein thioesterase that tethers its target proteins and modulates their acylation status. Furthermore, the functions of p53 in cell proliferation and Wnt/β-catenin signaling are significantly associated with the induction of RARRES3. Thus our findings provide a new insight into the molecular link between p53, protein acylation and Wnt/β-catenin signaling whereby RARRES3 plays a pivotal role in modulating the acylation status of signaling proteins.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Involvement of RARRES3 in the regulation of Wnt proteins acylation and signaling activities in human breast cancer cells

Hsu

Chan

et al. 2014

Cell Death Differ

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“…The techniques were performed as described previously (Doubravska et al ., 2011; Waaler et al ., 2012). For immunohistochemistry, dissected intestines were washed in ice‐cold PBS, fixed overnight in 4% (v/v) formaldehyde (Penta) and embedded in paraffin.…”

Section: Methodsmentioning

confidence: 99%

Wnt Signaling Inhibition Deprives Small Intestinal Stem Cells of Clonogenic Capacity

Janečková

Fafílek

Krausová

et al. 2016

Genesis

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SummaryThe Wnt pathway plays a crucial role in self‐renewal and differentiation of cells in the adult gut. In the present study, we revealed the functional consequences of inhibition of canonical Wnt signaling in the intestinal epithelium. The study was based on generation of a novel transgenic mouse strain enabling inducible expression of an N‐terminally truncated variant of nuclear Wnt effector T cell factor 4 (TCF4). The TCF4 variant acting as a dominant negative (dn) version of wild‐type (wt) TCF4 protein decreased transcription of β‐catenin‐TCF4‐responsive genes. Interestingly, suppression of Wnt/β‐catenin signaling affected asymmetric division of intestinal stem cells (ISCs) rather than proliferation. ISCs expressing the transgene underwent several rounds of division but lost their clonogenic potential and migrated out of the crypt. Expression profiling of crypt cells revealed that besides ISC‐specific markers, the dnTCF4 production downregulated expression levels of epithelial genes produced in other crypt cells including markers of Paneth cells. Additionally, in Apc conditional knockout mice, dnTCF activation efficiently suppressed growth of Apc‐deficient tumors. In summary, the generated mouse strain represents a convenient tool to study cell‐autonomous inhibition of β‐catenin‐Tcf‐mediated transcription. genesis 54:101–114, 2016. © 2016 The Authors genesis Published by Wiley Periodicals, Inc.

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“…2B). To verify these results in a different cell type, the b-catenin stabilization was visualized in L cells (15). In these mouse fibroblasts, monensin reduced Wnt3a-mediated accumulation of b-catenin in the cytoplasm and nucleus (Fig.…”

Section: Monensin Inhibits the Wnt Signaling Cascade At Multiple Levelsmentioning

confidence: 99%

Monensin Inhibits Canonical Wnt Signaling in Human Colorectal Cancer Cells and Suppresses Tumor Growth in Multiple Intestinal Neoplasia Mice

Tůmová

Pombinho

Vojtěchová

et al. 2014

Molecular Cancer Therapeutics

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The Wnt signaling pathway is required during embryonic development and for the maintenance of homeostasis in adult tissues. However, aberrant activation of the pathway is implicated in a number of human disorders, including cancer of the gastrointestinal tract, breast, liver, melanoma, and hematologic malignancies. In this study, we identified monensin, a polyether ionophore antibiotic, as a potent inhibitor of Wnt signaling. The inhibitory effect of monensin on the Wnt/b-catenin signaling cascade was observed in mammalian cells stimulated with Wnt ligands, glycogen synthase kinase-3 inhibitors, and in cells transfected with b-catenin expression constructs. Furthermore, monensin suppressed the Wnt-dependent tail fin regeneration in zebrafish and Wnt-or b-catenin-induced formation of secondary body axis in Xenopus embryos. In Wnt3a-activated HEK293 cells, monensin blocked the phoshorylation of Wnt coreceptor low-density lipoprotein receptor related protein 6 and promoted its degradation. In human colorectal carcinoma cells displaying deregulated Wnt signaling, monensin reduced the intracellular levels of b-catenin. The reduction attenuated the expression of Wnt signaling target genes such as cyclin D1 and SP5 and decreased the cell proliferation rate. In multiple intestinal neoplasia (Min) mice, daily administration of monensin suppressed progression of the intestinal tumors without any sign of toxicity on normal mucosa. Our data suggest monensin as a prospective anticancer drug for therapy of neoplasia with deregulated Wnt signaling. Mol Cancer Ther; 13(4); 812-22. Ó2014 AACR.

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Fatty acid modification of Wnt1 and Wnt3a at serine is prerequisite for lipidation at cysteine and is essential for Wnt signalling

Cited by 87 publications

References 56 publications

Involvement of RARRES3 in the regulation of Wnt proteins acylation and signaling activities in human breast cancer cells

Involvement of RARRES3 in the regulation of Wnt proteins acylation and signaling activities in human breast cancer cells

Wnt Signaling Inhibition Deprives Small Intestinal Stem Cells of Clonogenic Capacity

Monensin Inhibits Canonical Wnt Signaling in Human Colorectal Cancer Cells and Suppresses Tumor Growth in Multiple Intestinal Neoplasia Mice

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